The present invention relates to new compounds and pharmaceutically acceptable salts thereof.
More particularly, it relates to new compounds and pharmaceutically acceptable salts thereof which are useful as inhibitors of matrix metalloproteinases (hereinafter to be referred to as MMP) or the production of tumor necrosis factor a (hereinafter to be referred to as TNFxcex1), to pharmaceutical compositions comprising the same, to use of the same as medicaments, and to methods for using the same therapeutically in the treatment and/or the prevention of MMP- or TNFxcex1-mediated diseases.
Some piperazine compounds to be useful as metalloproteinase inhibitors, or the like are known (WO 97/20824, etc.).
One object of the present invention is to provide new and useful compounds and pharmaceutically acceptable salts thereof, and to provide a process for preparing said new compound and salts thereof, which have pharmacological activities such as MMP- or TNFxcex1-inhibitory activity and the like.
Another object of the present invention is to provide a pharmaceutical composition comprising, as an active ingredient, said compound or a pharmaceutically acceptable salt thereof.
A further object of the present invention is to provide use of said compounds and pharmaceutically acceptable salts thereof as medicaments for prophylactic and therapeutic treatment of MMP- or TNFxcex1-mediated diseases.
A still further object of the present invention is to provide a method for using the same for the treatment and/or the prevention of MMP- or TNFxcex1-mediated diseases in mammals, especially humans.
The compounds of the present invention have inhibitory activity on MMP or the production of TNFxcex1, and are useful for the treatment and/or prevention of diseases such as stroke, arthritis, cancer, tissue ulceration, decubitus ulcer, restenosis, periodontal disease, epidermolysis bullosa, scleritis, psoriasis and other diseases characterized by matrix metalloproteinase activity, as well as AIDS, sepsis, septic shock and other diseases caused by the production of TNFxcex1.
There are a number of structurally related metalloproteases which effect the breakdown of structural proteins. Matrix-degrading metalloproteases, such as gelatinase (MMP-2, MMP-9), stromelysin (MMP-3) and collagenase (MMP-1, HMP-8, MMP-13), are involved in tissue matrix degradation and have been implicated in many pathological conditions involving abnormal connective tissue and basement membrane matrix metabolism, such as arthritis (e.g., osteoarthritis and rheumatoid arthritis), cerebral diaease (e.g., stroke, etc.), tissue ulceration (e.g., corneal, epidermal and gastric ulcerations), abnormal wound healing, periodontal disease, bone disease (e.g., Paget""s disease and osteoporosis), tumor metastasis or invasion and HIV-infection.
A tumor necrosis factor is recognized to be involved in many infections and autoimmime diseases. Furthermore, it has been shown that TNF is the prime mediator of the inflammatory response seen in sepsis and septic shock.
The object compounds of the present invention are novel and can be represented by the following formula (I): 
wherein
A is a sulfonyl or a carbonyl;
R1 is an optionally substituted aryl, an optionally substituted heterocyclic group, an optionally substituted lower alkyl or an optionally substituted lower alkenyl;
R2 is a hydrogen, an optionally substituted lower alkyl, an optionally substituted aryl or an optionally substituted heterocyclic group;
R3 is an optionally substituted lower alkyl, an optionally substituted lower alkoxy, an optionally substituted aryloxy, an optionally substituted lower alkenyl, an optionally substituted aryl, an optionally substituted heterocyclic group or an optionally substituted amino:
R4 is a hydrogen, an optionally substituted lower alkyl, an optionally substituted aryl or an optionally substituted heterocyclic group;
R5 is a hydrogen, an optionally substituted lower alkyl, an optionally substituted aryl or an optionally substituted heterocyclic group; and
R10 is a hydroxy or a protected hydroxy,
provided that when Axe2x80x94R3 is methylsulfonyl, then R1 is an aryl substituted by a substituent selected from the group consisting of halogen, cyano, nitro, amino, acylamino, lower alkylamino, carbamoyl, hydroxy, lower alkoxy, phenoxy, lower alkyl, aryl and heterocyclic group, an optionally substituted heterocyclic group, an optionally substituted lower alkyl or an optionally substituted lower alkenyl, and the above-mentioned heterocyclic group is each selected from the group consisting of
unsaturated 3- to 8-membered heteromonocyclic group containing 1 to 4 nitrogen atoms,
saturated 3- to 8-membered heteromonocyclic group containing 1 to 4 nitrogen atoms,
unsaturated condensed 7- to 13-membered heterocyclic group containing 1 to 5 nitrogen atoms,
unsaturated 3- to 8-membered heteromonocyclic group containing 1 or 2 oxygen atoms and 1 to 3 nitrogen atoms,
saturated 3- to 8-membered heteromonocyclic group containing 1 or 2 oxygen atoms and 1 to 3 nitrogen atoms,
unsaturated condensed 7- to 13-membered heterocyclic group containing 1 or 2 oxygen atoms and 1 to 3 nitrogen atoms,
unsaturated 3- to 8-membered heteromonocyclic group containing 1 or 2 sulfur atoms and 1 to 3 nitrogen atoms,
saturated 3- to 8-membered heteromonocyclic group containing 1 or 2 sulfur atoms and 1 to 3 nitrogen atoms,
unsaturated 3- to 8-membered heteromonocyclic group containing sulfur atom,
unsaturated 3- to 8-membered heteromonocyclic group containing oxygen atom,
saturated 3- to 8-membered heteromonocyclic group containing oxygen atom,
unsaturated condensed 7- to 13-membered heterocyclic group containing 1 or 2 sulfur atoms and 1 to 3 nitrogen atoms and
unsaturated condensed 7- to 13-membered heterocyclic group containing 1 or 2 oxygen atoms,
and a pharmaceutically acceptable salt thereof.
The object compounds of the present invention can be prepared by the following processes. 
In the above formulas (II), (III), (IV), (V), (VI), (VII), (VIII), (X), (XI), (XII), (XIII), (XIV), (XV), (XVI), (XVIII), (XIX), (XX), (XXI) and (XXII), A, R1, R2, R3, R4 and R5 are as defined above, R10a is a protected hydroxy, X is a leaving group, R1a is a heterocyclic group having a substituent which is aryl substituted by acyloxy, R1b is a heterocyclic group having a substituent which is aryl substituted by hydroxy, R1c is a heterocyclic group having a substituent which is aryl substituted by cyanoalkyloxy, R1d is a heterocyclic group having a substituent which is aryl substituted by alkoxycarbonylalkyloxy, R3a is an alkyl substituted by halogen, R3b is a di(lower)alkylamino(lower)alkyl, an N-containing heterocyclic-(lower)-alkyl or an optionally substituted heterocyclic-thio(lower)alkyl, R3c is a protected carboxy(lower)alkyl or a protected carboxy(lower)alkyl-amino, R3d is a carboxy(lower)alkyl or a carboxy(lower)alkylamino, R3e is an N-containing heterocyclic-carbonyl(lower)alkyl, an optionally substituted amino-carbonyl(lower)alkyl or an optionally substituted amino-carbonyl(lower)alkylamino, R3f is a hydroxy(lower)alkyl, and R11 is a di(lower)alkylamino, an N-containing heterocyclic group or an optionally substituted heterocyclic-thiol. Heterocyclic group, aryl, acyl, alkyl, alkoxy, protected oxy and halogen in the R1a, R1b, R1c, R1d, R3a, R3b, R3c, R3d, R3e, R3f and R11 are as defined below.
The starting compounds (II), (VI), (XIV) and (XVI) can be prepared according to the following Preparations or by a conventional method.
Suitable pharmaceutically acceptable salts of the object compounds may be conventional non-toxic salts and include an acid addition salt such as an organic acid salt (e.g., acetate, trifluoroacetate, maleate, tartrate, fumarate, methanesulfonate, benzenesulfonate, formate, toluenesulfonate, etc.), an inorganic acid salt (e.g., hydrochloride, hydrobromide, hydroiodide, sulfate, nitrate, phosphate, etc.), or a salt with a base such as an amino acid (e.g., arginine, aspartic acid, glutamic acid, etc.), an alkali metal salt (e.g., sodium salt, potassium salt, etc.), an alkaline earth metal salt (e.g., calcium salt, magnesium salt, etc.), an ammonium salt, an organic base salt (e.g., trimethylamine salt, triethylamine salt, pyridine salt, picoline salt, dicyclohexylamine salt, N,Nxe2x80x2-dibenzyl-ethylenediamine salt, etc.), or the like.
The object compounds and pharmaceutically acceptable salts thereof may include solvates such as enclosure compounds (e.g., hydrate, etc.).
Suitable examples and illustrations of the various definitions, which the present invention includes within its scope and which are shown in the above and subsequent descriptions of the present specification, are as follows.
Suitable xe2x80x9carylxe2x80x9d in the term xe2x80x9coptionally substituted arylxe2x80x9d and xe2x80x9coptionally substituted aryloxyxe2x80x9d includes an aryl having 6 to 10 carton atoms, such as phenyl, tolyl, xylyl, cumenyl, mesityl, naphthyl and the like, preferably phenyl, and may have one or more substituents. Examples of the substituents for substituted aryl are halogen, cyano, nitro, amino, acylamino, lower alkylamino, carbamoyl, hydroxy, lower alkoxy, aryloxy, lower alkyl, optionally substituted aryl, optionally substituted heterocyclic group and the like, preferably halogen, nitro and lower alkoxy (e.g., methoxy, etc.).
Suitable xe2x80x9cheterocyclic groupxe2x80x9d in the term xe2x80x9coptionally substituted heterocyclic groupxe2x80x9d means saturated or unsaturated, 3- to 8-membered monocyclic or polycyclic heterocyclic group containing at least one hetero atom such as oxygen atom, sulfur atom, nitrogen atom and the like.
More preferable heterocyclic groups are:
unsaturated 3- to 8-membered, preferably 5- or 6-membered, heteromonocyclic group containing 1 to 4 nitrogen atoms, for example, pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, pyridyl and its N-oxide, pyrimidyl, pyrazinyl, pyridazinyl, triazolyl (e.g., 4H-1,2,4-triazolyl, 1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl, etc.), tetrazolyl (e.g., 1H-tetrazolyl, 2H-tetrazolyl, etc.), dihydrotriazinyl (e.g., 4,5-dihydro-1,2,4-triazinyl, 2,5-dihydro-1,2,4-triazinyl, etc.), and the like;
saturated 3- to 8-membered, preferably 5- or 6-membered, heteromonocyclic group containing 1 to 4 nitrogen atoms, for example, azetidinyl, pyrrolidinyl, imidazolidinyl, piperidinyl, piperidino, pyrazolidinyl, piperazinyl, and the like;
unsaturated condensed 7- to 13-membered, preferably 9- or 10-membered, heterocyclic group containing 1 to 5 nitrogen atoms, for example, indolyl, isoindolyl, indolizinyl, benzimidazolyl, quinolyl, isoquinolyl, indazolyl, benzotriazolyl, tetrazolopyridyl, tetrazolopyridazinyl (e.g., tetrazolo[1,5-b]pyridazinyl, etc.), dihydrotriazolopyridazinyl, and the like;
unsaturated 3- to 8-membered, preferably 5- or 6-membered, heteromonocyclic group containing 1 or 2 oxygen atoms and 1 to 3 nitrogen atoms, for example, oxazolyl, isoxazolyl, oxadiazolyl (e.g., 1,2,4oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,5-oxadiazolyl, etc.), and the like;
saturated 3- to 8-membered, preferably 5- or 6-membered, heteromonocyclic group containing 1 or 2 oxygen atoms and 1 to 3 nitrogen atoms, for example, morpholinyl, morpholino, and the like;
unsaturated condensed 7- to 13-membered, preferably 9- or 10-membered, heterocyclic group containing 1 or 2 oxygen atoms and 1 to 3 nitrogen atoms, for example, benzoxazolyl, benzoxadiazolyl, and the like;
unsaturated 3- to 8-membered, preferably 5- or 6-membered, heteromonocyclic group containing 1 or 2 sulfur atoms and 1 to 3 nitrogen atoms, for example, thiazolyl, 1,2-thiazolyl, thiazolinyl, thiadiazolyl (e.g., 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,2,3-thiadiazolyl, etc.), and the like;
saturated 3- to 8-membered, preferably 5- or 6-membered, heteromonocyclic group containing 1 or 2 sulfur atoms and 1 to 3 nitrogen atoms, for example, thiazolidinyl, and the like;
unsaturated 3- to 8-membered, preferably 5- or 6-membered, heteromonocyclic group containing sulfur atom, for example, thienyl, and the like;
unsaturated 3- to 8-membered, preferably 5- or 6-membered, heteromonocyclic group containing oxygen atom, for example, furyl, and the like;
saturated 3- to 8-membered, preferably 5- or 6-membered, heteromonocyclic group containing oxygen atom, for example, oxolanyl, and the like;
unsaturated condensed 7- to 13-membered, preferably 9- or 10-membered, heterocyclic group containing 1 or 2 sulfur atoms and 1 to 3 nitrogen atoms, for example, benzothiazolyl, benzothiadiazolyl, and the like;
unsaturated condensed 7- to 13-membered, preferably 9- or 10-membered, heterocyclic group containing 1 or 2 oxygen atoms, for example, benzodihydrofuranyl, benzodioxolenyl, and the like;
The most preferable heterocyclic groups may be unsaturated 5- or 6-membered heteromonocyclic group containing 1 to 4 nitrogen atoms, saturated 5- or 6-membered, heteromonocyclic group containing 1 to 4 nitrogen atoms, unsaturated 5- or 6-membered heteromonocyclic group containing 1 or 2 oxygen atoms and 1 to 3 nitrogen atoms, saturated 5- or 6-membered heteromonocyclic group containing 1 or 2 oxygen atoms and 1 to 3 nitrogen atoms, unsaturated 5- or 6-membered heteromonocyclic group containing 1 or 2 sulfur atoms and 1 to 3 nitrogen atoms, unsaturated 5- or 6-membered heteromonocyclic group containing a sulfur atom, and unsaturated 9- or 10-membered heterobicyclic group containing 1 or 2 oxygen atoms.
These heterocyclic groups may have one or more substituents. Examples of the substituents for substituted heterocyclic group are halogen, cyano, nitro, amino, acylamino, lower alkylamino, carbamoyl, hydroxy, lower alkoxy, aryloxy, lower alkyl, aryl, optionally substituted heterocyclic group, haloaryl, hydroxyaryl, lower alkoxyaryl, lower alkylaryl, nitroaryl, biphenylyl, aryloxyaryl, trihaloalkylaryl, cyano(lower)alkoxyaryl, cyanoaryl, cyano(lower)alkylaryl, lower alkanoyloxyaryl, lower alkanoyloxy(lower)alkylaryl, di(lower)alkylaminosulfonylaryl, hydroxy(lower)alkylaryl, lower alkoxycarbonylaryl, lower alkoxycarbonyl(lower)alkoxyaryl, lower alkoxysulfonyloxyaryl, aryl substituted by halogen and hydroxy, aryl substituted by halogen and alkanoyloxy, aryl substituted by halogen and lower alkoxy, lower alkyl-heterocyclic group and aryl-heterocyclic group and the like, preferably halogen; phenyl; halophenyl; hydroxyphenyl; lower alkoxyphenyl; lower alkylphenyl; nitrophenyl; biphenylyl; phenoxyphenyl; trihalo (lower) alkylphenyl; cyano (lower) alkoxyphenyl; cyanophenyl; cyano(lower)alkylphenyl; lower alkanoyloxyphenyl; lower alkanoyloxy(lower)alkylphenyl; di(lower)alkylaminosulfonylphenyl; hydroxy(lower)alkylphenyl; lower alkoxycarbonylphenyl; lower alkoxycarbonyl(lower)alkoxyphenyl; lower alkoxysulfonyloxyphenyl; phenyl substituted by halogen and hydroxy, phenyl substituted by halogen and lower alkanoyloxy; phenyl substituted by halogen and lower alkoxy; heterocyclic group selected from the group consisting of unsaturated 9- or 10-membered heterobicyclic group containing 1 or 2 oxygen atoms, unsaturated 5- or 6-membered heteromonocyclic group containing 1 to 4 nitrogen atoms,
unsaturated 5- or 6-membered heteromonocyclic group containing 1 or 2 oxygen atoms and 1 to 3 nitrogen atoms and
unsaturated 5- or 6-membered heteromonocyclic group containing 1 or 2 sulfur atoms and 1 to 3 nitrogen atoms;
and a lower alkyl- or (phenyl-)heterocyclic group, said heterocyclic group being unsaturated 5- or 6-membered heteromonocyclic group containing 1 or 2 oxygen atoms and 1 to 3 nitrogen atoms.
Suitable xe2x80x9clower alkylxe2x80x9d in the term xe2x80x9coptionally substituted lower alkylxe2x80x9d is a straight or branched alkyl having 1 to 6 carbon atoms, and exemplified by methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, hexyl and the like, preferably methyl and propyl, which may have one or more substituents. Examples of the substituents for substituted alkyl are halogen, cyano, nitro, acylamino, carbamoyl, hydroxy, lower alkoxy, optionally substituted aryloxy, optionally substituted aryl, heterocyclic group, heterocyclic-carbonyl, lower alkylcarbamoyl, carboxy, protected carboxy, di(lower)alkylamino, lower alkylamino, protected amino, arylcarbonylamino, heterocyclic-carbonylamino, lower alkanoylamino, lower alkylsulfonylamino, di(lower) alkylaminosulfonylamino, heterocyclicsulfonylamino, heterocyclic-thio, lower alkylheterocyclic-thio and the like, preferably halogen for R1, and halogen, carbamoyl, heterocyclic group, heterocyclic-carbonyl, lower alkylcarbamoyl, carboxy, protected carboxy, di(lower)alkylamino, lower alkylamino, protected amino, arylcarbonylamino, heterocyclic-carbonylamino, lower alkanoylamino, lower alkylsulfonylamino, di(lower)alkylaminosulfonylamino, heterocyclicsulfonylamino, heterocyclic-thio and lower alkylheterocyclic-thio for R3.
Suitable xe2x80x9clower alkenylxe2x80x9d in the term xe2x80x9coptionally substituted lower alkenylxe2x80x9d is a straight or branched alkenyl having 2 to 6 carbon atoms, and exemplified by ethenyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 1-pentenyl, 2-pentenyl and the like, preferably ethenyl, which may have one or more substituents. Examples of the substituents for substituted alkyl are halogen, cyano, nitro, acylamino, lower alkylamino, carbamoyl, hydroxy, lower alkoxy, optionally substituted aryloxy, optionally substituted aryl, heterocyclic group, heterocyclic-carbonyl and the like, preferably aryl (e.g., phenyl, etc.) for R1, and heterocyclic group (e.g., pyridyl, etc.) for R3.
Suitable xe2x80x9clower alkoxyxe2x80x9d in the term xe2x80x9coptionally substituted alkoxyxe2x80x9d is a straight or branched alkenyl having 1 to 6 carbon atoms, and exemplified by methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tert-butoxy, pentyloxy, tert-pentyloxy, hexyloxy and the like, preferably methoxy, which may have one or more substituents. Examples of the substituents for substituted alkoxy are halogen, cyano, nitro, acylamino, lower alkylamino, carbamoyl, hydroxy, lower alkoxy, optionally substituted aryloxy, optionally substituted aryl, heterocyclic group, heterocyclic-carbonyl and the like, preferably aryl (e.g., fluorenyl, etc.).
Suitable xe2x80x9coptionally substituted aminoxe2x80x9d includes a group of the formula: 
wherein R8 and R9 are the same or different and each is hydrogen, lower alkyl, carboxy(lower)alkyl, lower alkoxycarbonyl(lower)alkyl, carbamoyl(lower)alkyl, hydroxy(lower)alkyl, aryl or cyclo(lower)alkyl.
Suitable xe2x80x9cprotected hydroxyxe2x80x9d includes hydroxy protected by a conventional protective group, for example, substituted lower alkoxy such as lower alkoxy(lower)alkoxy (e.g., methoxymethoxy), lower alkoxy(lower)alkoxy(lower)alkoxy (e.g., methoxyethoxymethoxy) and substituted or unsubstituted aryl(lower)alkoxy (e.g., benzyloxy, nitrobenzyloxy); acyloxy such as lower alkanoyloxy (e.g., acetoxy, propionyloxy, pivaloyloxy), aroyloxy (e.g., benzoyloxy, fluorenecarbonyloxy), lower alkoxycarbonyloxy (e.g., methoxycarbonyloxy, ethoxycarbonyloxy, propoxycarbonyloxy, isopropoxycarbonyloxy, butoxycarbonyloxy, isobutoxycarbonyloxy, tert-butoxycarbonyloxy, pentyloxycarbonyloxy, hexyloxycarbonyloxy), substituted or unsubstituted aryl(lower)alkoxycarbonyloxy (e.g., benzyloxycarbonyloxy, bromobenzyloxycarbonyloxy), arenesulfonyloxy (e.g., benzenesulfonyloxy, tosyloxy) and alkanesulfonyloxy (e.g., methanesulfonyloxy, ethanesulfonyloxy); tri(lower)alkylsilyloxy (e.g., trimethylsilyloxy); tetrahydropyranyloxy; and the like.
The term xe2x80x9clowerxe2x80x9d is intended to mean 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms, unless otherwise indicated.
Suitable xe2x80x9chalogenxe2x80x9d includes fluorine, bromine, chlorine and iodine.
Suitable acyl moiety of xe2x80x9cacylaminoxe2x80x9d includes acyl such as aliphatic acyl, aromatic acyl, heterocyclic acyl and aliphatic acyl substituted by aromatic or heterocyclic group(s) derived from carboxylic, carbonic, sulfonic and carbamic acids.
The aliphatic acyl includes saturated or unsaturated, acyclic or cyclic ones, for example, alkanoyl such as lower alkanoyl (e.g., formyl, acetyl, propionyl, butylyl, isobutylyl, valeryl, isovaleryl, pivaloyl, hexanoyl, etc.), alkylsulfonyl such as lower alkylsulfonyl (e.g., mesyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, butylsulfonyl, isobutylsulfonyl, pentylsulfonyl, hexylsulfonyl, etc.), carbamoyl, N-alkylcarbamoyl (e.g., methylcarbamoyl, ethylcarbamoyl, etc.), alkoxycarbonyl such as lower alkoxycarbonyl (e.g., methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, tert-butoxycarbonyl, etc.), alkenyloxycarbonyl such as lower alkenyloxycarbonyl (e.g., vinyloxycarbonyl, allyloxycarbonyl, etc.), alkenoyl such as lower alkenoyl (e.g., acryloyl, methacryloyl, crotonoyl, etc.), cyclalkanecarbonyl such as cyclo(lower)alkanecarbonyl (e.g., cyclopropanecarbonyl, cyclopentanecarbonyl, cyclohexanecarbonyl, etc.), and the like.
The aromatic acyl may include C6-C10 aroyl (e.g., benzoyl, toluoyl, xyloyl, etc.), N-(C6-C10)arylcarbamoyl (e.g., N-phenylcarbamoyl, N-tolylcarbamoyl, N-naphthylcarbamoyl, etc.), C6-C10 arenesulfonyl (e.g., benzenesulfonyl, tosyl, etc.), and the like.
The heterocyclic acyl may include heterocyclic-carbonyl (e.g., furoyl, thenoyl, nicotinoyl, isonicotinoyl, thiazolylcarbonyl, thiadiazolylcarbonyl, tetrazolylcarbonyl, etc.), and the like.
The aliphatic acyl substituted by aromatic group(s) may include aralkanoyl such as phenyl(lower)alkanoyl (e.g., phenylacetyl, phenylpropionyl, phenylhexanoyl, etc.), aralkoxycarbonyl such as phenyl(lower)alkoxycarbonyl (e.g., benzyloxycarbonyl, phenethyloxycarbonyl, etc.), aryloxyalkanoyl such as phenoxy(lower)alkanoyl (e.g., phenoxyacetyl, phenoxypropionyl, etc.), and the like.
The aliphatic acyl substituted by heterocyclic group(s) may include heterocyclic-alkanoyl such as heterocyclic-(lower)alkanoyl (e.g., thienylacetyl, imidazolylacetyl, furylacetyl, tetrazolylacetyl, thiazolylacetyl, thiadiazolylacetyl, thienylpropionyl, thiadiazolylpropionyl, etc.), and the like.
These acyl groups may be further substituted by one or more suitable substituents such as nitro and the like, and preferable acyl having such substituent(s) may be nitroaralkoxycarbonyl (e.g., nitrobenzyloxycarbonyl, etc.) and the like.
Suitable xe2x80x9clower alkylxe2x80x9d and lower alkyl moiety of xe2x80x9clower alkylaminoxe2x80x9d, xe2x80x9clower alkylarylxe2x80x9d, xe2x80x9ctrihaloalkylarylxe2x80x9d, xe2x80x9ccyano(lower)alkylarylxe2x80x9d, xe2x80x9clower alkanoyloxy(lower)alkylarylxe2x80x9d, xe2x80x9clower alkylsulfonyloxyarylxe2x80x9d, xe2x80x9cdi(lower)alkylaminosulfonylarylxe2x80x9d, xe2x80x9chydroxy(lower)alkylarylxe2x80x9d, xe2x80x9clower alkyl-heterocyclic groupxe2x80x9d, xe2x80x9clower alkycarbamoylxe2x80x9d, xe2x80x9cdi(lower)alkylaminoxe2x80x9d, xe2x80x9clower alkylsulfonylaminoxe2x80x9d xe2x80x9cdi(lower)alkylaminosulfonylaminoxe2x80x9d, xe2x80x9clower alkylheterocyclic-thioxe2x80x9d, xe2x80x9ccarboxy(lower)alkylxe2x80x9d, xe2x80x9clower alkoxycarbonyl(lower)alkylxe2x80x9d, xe2x80x9ccarbamoyl(lower)alkylxe2x80x9d and xe2x80x9chydroxy(lower)alkylxe2x80x9d are the same as lower alkyl defined above with regard to xe2x80x9coptionally substituted lower alkylxe2x80x9d.
Suitable xe2x80x9clower alkoxyxe2x80x9d and lower alkoxy moiety of xe2x80x9clower alkoxyarylxe2x80x9d, xe2x80x9ccyano(lower)alkoxyarylxe2x80x9d, xe2x80x9clower alkoxycarbonylarylxe2x80x9d, xe2x80x9clower alkoxycarbonyl(lower)alkoxyarylxe2x80x9d and xe2x80x9clower alkoxycarbonyl(lower)alkylxe2x80x9d are the same as alkoxy defined above with regard to xe2x80x9coptionally substituted alkoxyxe2x80x9d.
Suitable xe2x80x9carylxe2x80x9d and aryl moiety of xe2x80x9caryloxyxe2x80x9d, xe2x80x9chaloarylxe2x80x9d, xe2x80x9chydroxyarylxe2x80x9d, xe2x80x9clower alkoxyarylxe2x80x9d, xe2x80x9clower alkylarylxe2x80x9d, xe2x80x9cnitroarylxe2x80x9d, xe2x80x9caryloxyarylxe2x80x9d, xe2x80x9ctrihaloalkylarylxe2x80x9d, xe2x80x9ccyano(lower)alkoxyarylxe2x80x9d, xe2x80x9ccyanoarylxe2x80x9d, xe2x80x9ccyano(lower)alkylarylxe2x80x9d, xe2x80x9clower alkanoyloxyarylxe2x80x9d, xe2x80x9clower alkanoyloxy(lower)alkylarylxe2x80x9d, xe2x80x9cdi(lower)alkylaminosulfonylarylxe2x80x9d, xe2x80x9chydroxy(lower)alkylarylxe2x80x9d, xe2x80x9cloweralkoxycarbonylarylxe2x80x9d, xe2x80x9clower alkoxycarbonyl(lower)alkoxyarylxe2x80x9d, xe2x80x9clower alkylsulfonyloxyarylxe2x80x9d, xe2x80x9caryl substituted by halogen and hydroxyxe2x80x9d, xe2x80x9caryl substituted by halogen and alkanoyloxyxe2x80x9d, xe2x80x9caryl substituted by halogen and lower alkoxyxe2x80x9d, xe2x80x9carylheterocyclic groupxe2x80x9d and xe2x80x9carylcarbonylaminoxe2x80x9d are the same as aryl defined above with regard to xe2x80x9coptionally substituted arylxe2x80x9d.
Suitable xe2x80x9cheterocyclic groupxe2x80x9d of the substituent and heterocyclic group moiety of xe2x80x9cheterocyclic-carbonylxe2x80x9d, xe2x80x9clower alkyl-heterocyclic groupxe2x80x9d, xe2x80x9caryl-heterocyclic groupxe2x80x9d, xe2x80x9cheterocyclic carbonylaminoxe2x80x9d, xe2x80x9cheterocyclic-sulfonylaminoxe2x80x9d, xe2x80x9cheterocyclic-thioxe2x80x9d, xe2x80x9clower alkylheterocyclic-thioxe2x80x9d, xe2x80x9cheterocyclic(lower)alkylxe2x80x9d and xe2x80x9cheterocyclic-thioxe2x80x9d are the same as heterocyclic group defined above with regard to xe2x80x9coptionally substituted heterocyclic groupxe2x80x9d.
Suitable halo moiety of xe2x80x9chaloarylxe2x80x9d and xe2x80x9ctrihaloalkylarylxe2x80x9d is halogen defined above.
Suitable alkanoyl moiety of xe2x80x9clower alkanoyloxyarylxe2x80x9d, xe2x80x9clower alkanoyloxy(lower)alkylxe2x80x9d, xe2x80x9calkanoyloxyxe2x80x9d and xe2x80x9clower alkanoylaminoxe2x80x9d is a straight or branched alkanoyl having 1 to 10, preferably 1 to 6, carbon atoms. Such group includes, for example, formyl, acetyl, propionyl, isopropionyl, butyryl, isobutyryl, valeryl, pivaloyl, hexanoyl and the like, preferably acetyl.
Suitable xe2x80x9cprotected carboxyxe2x80x9d includes esterified carboxy wherein xe2x80x9cesterified carboxyxe2x80x9d is as defined below.
Suitable examples of the ester moiety of the esterified carboxy are lower alkyl ester (e.g., methyl ester, ethyl ester, propyl ester, isopropyl ester, butyl ester, isobutyl ester, tert-butyl ester, pentyl ester, hexyl ester, etc.) and the like, which may have at least one suitable substituent. Examples of the substituted lower alkyl ester are lower alkanoyloxy(lower)alkyl ester [e.g., acetoxymethyl ester, propionyloxymethyl ester, butyryloxymethyl ester, valeryloxymethyl ester, pivaloyloxymethyl ester, hexanoyloxymethyl ester, 1-(or 2-)acetoxyethyl ester, 1-(or 2- or 3-)acetoxypropyl ester, 1-(or 2- or 3- or 4-)acetoxybutyl ester, 1-(or 2-)propionyloxyethyl ester, 1-(or 2- or 3-)propionyloxypropyl ester, 1-(or 2-)butyryloxyethyl ester, 1-(or 2-)isobutyryloxyethyl ester, 1-(or 2-)pivaloyloxyethyl ester, 1-(or 2-)hexanoyloxyethyl ester, isobutyryloxymethylester, 2-ethylbutyryloxymethyl ester, 3,3-dimethylbutyryloxymethylester, 1-(or 2-)pentanoyloxyethyl ester, etc.], lower alkanesulfonyl(lower)alkyl ester (e.g., 2-mesylethyl ester, etc.), mono(or di or tri)halo(lower)alkyl ester (e.g., 2-iodoethyl ester, 2,2,2-trichloroethyl ester, etc.); lower alkoxycarbonyloxy(lower)alkyl ester [(e.g., methoxycarbonyloxymethyl ester, ethoxycarbonyloxymethyl ester, propoxycarbonyloxymethyl ester, tert-butoxycarbonyloxymethyl ester, 1-(or 2-)methoxycarbonyloxyethyl ester, 1-(or 2-)ethoxycarbonyloxyethyl ester, 1-(or 2-)isopropoxycarbonyloxyethyl ester, etc.], phthalidylidene(lower)alkyl ester, (5-lower alkyl-2-oxo-1,3-dioxol-4-yl)(lower)alkyl ester [e.g., (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl ester, (5-ethyl-2-oxo-1,3-dioxol-4-yl)methyl ester, (5-propyl-2-oxo-1,3-dioxol-4-yl)ethyl ester, etc.]; lower alkenyl ester (e.g., vinyl ester, alkyl ester, etc.); lower alkynyl ester (e.g., ethynyl ester, propynyl ester, etc.); ar(lower)alkyl ester which may have at least one suitable substituent (e.g., benzyl ester, 4-methoxybenzyl ester, 4-nitrobenzyl ester, phenethyl ester, trityl ester, benzhydryl ester, bis(methoxyphenyl)methyl ester, 3,4-dimethoxybenzyl ester, 4-hydroxy-3,5-di-tert-butylbenzyl ester, etc.); aryl ester which may have at least one suitable substituent (e.g., phenyl ester, 4-chlorophenyl ester, tolyl ester, tert-butylphenyl ester, xylyl ester, mesityl ester, cumenyl ester, etc.); phthalidyl ester; and the like.
More preferable examples of the protected carboxy thus defined may be C2-C4 alkenyloxycarbonyl and phenyl(or nitrophenyl) (C1-C4) alkoxycarbonyl, and the most preferable one may be ethoxycarbonyl.
Suitable xe2x80x9camino-protective groupxe2x80x9d includes xe2x80x9cacylxe2x80x9d mentioned above.
More preferable examples of xe2x80x9camino-protective groupxe2x80x9d are C2-C4 alkoxycarbonyl and phenyl(or nitrophenyl) (C1-C4)alkoxycarbonyl, and the most preferable one is tert-butoxycarbonyl.
Suitable xe2x80x9ccyclo(lower)alkylxe2x80x9d is, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.
Suitable xe2x80x9cleaving groupxe2x80x9d includes halogen as mentioned above, acyloxy such as sulfonyloxy (e.g., mesyloxy, tosyloxy, etc.), alkoxy (e.g., tert-butoxy, etc.), aralkoxy (e.g., benzyloxy, etc.), and the like.
Of the object compounds (I),
(1) the preferred one may be the compound of the formula (I) wherein
R2 is a hydrogen or an optionally substituted lower alkyl, and
R4 is a hydrogen or an optionally substituted lower alkyl,
(2) the more preferred one may be the compound of the formula (I) wherein
A is a sulfonyl or a carbonyl;
R1 is an aryl optionally substituted by a substituent selected from the group consisting of halogen, cyano, nitro, amino, acylamimo, lower alkylamino, carbamoyl, hydroxy, lower alkoxy, phenoxy, lower alkyl, aryl and heterocyclic group; a heterocyclic group optionally substituted by a substituent selected from the group consisting of halogen, cyano, nitro, amino, acylamino, lower alkylamino, carbamoyl, hydroxy, lower alkoxy, aryloxy, lower alkyl, aryl, heterocyclic group, haloaryl, hydroxyaryl, lower alkoxyaryl, lower alkylaryl, nitroaryl, biphenylyl, aryloxyaryl, trihaloalkylaryl, cyano(lower)alkoxyaryl, cyanoaryl, cyano(lower)alkylaryl, lower alkanoyloxyaryl, lower alkanoyloxy(lower)alkylaryl, di(lower)alkylaminosulfonylaryl, hydroxy(lower)alkylaryl, lower alkoxycarbonylaryl, lower alkoxycarbonyl(lower)alkoxyaryl, lower alkylsulfonyloxyaryl, aryl substituted by halogen and hydroxy, aryl substituted by halogen and alkanoyloxy, aryl substituted by halogen and lower alkoxy, lower alkyl-heteromonocyclic group and arylheterocyclic group; a lower alkyl optionally substituted by halogen; or a lower alkenyl optionally substituted by aryl;
R2 is a hydrogen or an optionally substituted lower alkyl;
R3 is a lower alkyl optionally substituted by a substituent selected from the group consisting of halogen, heterocyclic group, carbamoyl, lower alkylcarbamoyl, carboxy, protected carboxy, heterocyclic-carbonyl, di(lower)alkylamino, protected amino, arylcarbonylamino, heterocyclic-carbonylamino, lower alkanoylamino, lower alkylsulfonylamino, di(lower)alkylaminosulfonylamino, heterocyclic-sulfonyl amino, heterocyclic-thio, lower alkylheterocyclic-thio and heterocyclic-thio; a lower alkoxy; an aryloxy; an aryl(lower)alkoxy; an optionally substituted lower alkenyl; an optionally substituted heterocyclic group; or a group of the formula: 
wherein R8 and R9 are the same or different and each is hydrogen, lower alkyl, carboxy(lower)alkyl, lower alkoxycarbonyl(lower)alkyl, carbamoyl(lower)alkyl, hydroxy(lower)alkyl, aryl, cyclo(lower)alkyl or heterocyclic-(lower)alkyl;
R4 is a hydrogen or an optionally substituted lower alkyl;
R5 is a hydrogen, an optionally substituted lower alkyl, an optionally substituted aryl or an optionally substituted heterocyclic group and
R10 is a hydroxy or a protected hydroxy; and
(3) the most preferred one may be the compound of the formula (I) wherein
A is a sulfonyl or a carbonyl;
R1 is a thienyl substituted by a substituent selected from the group consisting of halogen, phenyl, halophenyl, hydroxyphenyl, lower alkoxyphenyl, lower alkylphenyl, nitrophenyl, biphenylyl, phenoxyphenyl, trihalo(lower)alkylphenyl, cyano(lower)alkoxyphenyl, cyanophenyl, cyano(lower)alkylphenyl, lower alkanoyloxyphenyl, lower alkanoyloxy(lower)alkylphenyl, di(lower)alkylaminosulfonylphenyl, hydroxy(lower)alkylphenyl, lower alkoxycarbonylphenyl, lower alkoxycarbonyl(lower)alkoxyphenyl, lower alkylsulfonyloxyphenyl, phenyl substituted by halogen and hydroxy, phenyl substituted by halogen and lower alkanoyloxy, phenyl substituted by halogen and lower alkoxy, thiazolyl, oxazolyl, pyridyl, benzodihydrofuranyl, benzodioxolenyl, lower alkyloxadiazolyl and phenyloxadiazolyl, a thiazolyl substituted by phenyl or a thiadiazolyl substituted by phenyl;
R2 is a hydrogen;
R3 is a lower alkyl, a halo(lower)alkyl, a morpholinyl(lower)alkyl, a piperidinyl(lower)alkyl, a pyridyl(lower)alkyl, a carbamoyl(lower)alkyl, a lower alkylcarbamoyl(lower)alkyl, a carboxy(lower)alkyl, a phenyl(lower)alkoxycarbonyl(lower)alkyl, a morpholinylcarbonyl(lower)alkyl, a di(lower)alkylamino(lower)alkyl, a phenyl(lower)alkoxycarbonylamino(lower)alkyl, a lower alkoxycarbonylamino(lower)alkyl, a benzoylamino(lower)alkyl, a pyridyl-carbonylamino(lower)alkyl, a lower alkanoylamino(lower)alkyl, a lower alkylsulfonylamino(lower)alkyl, a di(lower)alkylaminosulfonylamino(lower)alkyl, a pyridyl-sulfonylamino(lower)alkyl, a triazolylthio(lower)alkyl, an imidazolylthio(lower)alkyl, a thiazolylthio(lower)alkyl, a benzimidazolylthio(lower)alkyl, a lower alkyltriazolylthio(lower)alkyl, a lower alkoxy, a fluorenyl(lower)alkoxy, a phenoxy, a pyridyl(lower)alkenyl, a pyridyl, a piperidinyl, a thienyl substituted by oxazolyl, a mono-(or di-)(lower)alkylamino, a carboxy(lower)alkylamino, a lower alkoxycabonyl(lower)alkylamino, an N-(lower)alkyl-N-(lower)alkoxycabonyl(lower)alkylamino, a carbamoyl(lower)alkylamino, a hydroxy(lower)alkylamino, a phenylamino or a cyclo(lower)alkylamino;
R4 is a hydrogen;
R5 is a hydrogen and
R10 is a hydroxy.
The processes for preparing the object compounds are explained in detail in the following.
The compound (IV) or a salt thereof can be prepared by reacting the compound (II) or a salt thereof with the compound (III) or a salt thereof.
Suitable salts of the compounds (II), (III) and (IV) may be the same as those exemplified with respect to the compound (I).
The reaction is usually carried out in a conventional solvent such as water, acetone, dioxane, acetonitrile, chloroform, methylene chloride, ethylene chloride, tetrahydrofuran, ethyl acetate, N,N-dimethylformamide, pyridine and dichloromethane, a mixture thereof, or any other organic solvents which do not adversely affect the reaction.
This reaction can be carried out in the presence of an organic or inorganic base such as alkali metal (e.g., lithium, sodium, potassium, etc.), Alkaline earth metal (e.g., calcium, etc.), alkali metal hydride (e.g., sodium hydride, etc.), alkaline earth metal hydride (e.g., calcium hydride, etc.), alkali metal hydroxide (e.g., sodium hydroxide, potassium hydroxide, etc.), alkali metal carbonate (e.g., sodium carbonate, potassium carbonate, etc.), alkali metal bicarbonate (e.g., sodium bicarbonate, potassium bicarbonate, etc.), alkali metal alkoxide (e.g., sodium methoxide, sodium ethoxide, potassium tert-butoxide, etc.), alkali metal alkanoic acid (e.g., sodium acetate, etc.), trialkylamine (e.g., triethylamine, etc.), pyridine compound (e.g., pyridine, lutidine, picoline, 4-dimethylaminopyridine, etc.), quinoline, lithium diisopropylamide, and the like.
The reaction temperature is not critical, and the reaction is usually carried out under cooling to heating.
The compound (V) and a salt thereof can be prepared by eliminating the hydroxy protective group of the compound (IV) or a salt thereof.
Suitable salts of the compounds (IV) and (V) may be the same as those exemplified above with regard to the compound (I).
Suitable method of this elimination reaction includes conventional ones such as hydrolysis, reduction and the like.
The hydrolysis is preferably carried out in the presence of a base or an acid including Lewis acid.
Suitable base includes an inorganic base and an organic base such as an alkali metal (e.g., sodium, potassium, etc.), an alkaline earth metal (e.g., magnesium, calcium, etc.), the hydroxide or carbonate or hydrogencarbonate thereof, trialkylamine (e.g., trimethylamine, triethylamine, etc.), picoline, 1,5-diazabicyclo[4.3.0]non-5-one, and the like.
Suitable acid includes an organic acid (e.g., formic acid, acetic acid, propionic acid, trichloroacetic acid, trifluoroacetic acid, etc.), and an inorganic acid (e.g., hydrochloric acid, hydrobromic acid, sulfuric acid, hydrogen chloride, hydrogen bromide, etc.).
The elimination using Lewis acid such as trihaloacetic acid (e.g., trichloroacetic acid, trifluoroacetic acid, etc.) and the like is preferably carried out in the presence of cation trapping agent (e.g., anisole, phenol, etc.). This reaction is usually carried out without solvent.
Alternatively, the reaction may be carried out in a conventional solvent such as water, alcohol (e.g., methanol, ethanol, isopropyl alcohol, etc.), tetrahydrofuran, dioxane, toluene, methylene. chloride, ethylene dichloride, chloroform, N,N-dimethylformamide and N,N-dimethylacetamide, a mixture thereof, or any other organic solvents which do not adversely affect the reaction.
The reaction temperature is not critical and the reaction is usually carried out under cooling to warming.
The reduction is carried out in a conventional manner, including chemical reduction and catalytic reduction.
Suitable reducing reagents to be used in chemical reduction are a hydride (e.g., hydrogen iodide, hydrogen sulfide, lithium aluminum hydride, sodium borohydride, sodium cyanoborohydride, etc.), or a combination of a metal (e.g., tin, zinc, iron, etc.) or a metallic compound (e.g., chromium chloride, chromium acetate, etc.) and an organic acid or an inorganic acid (e.g., formic acid, acetic acid, propionic acid, trifluoroacetic acid, p-toluenesulfonic acid, hydrochloric acid, hydrobromic acid, etc.).
Suitable catalyst to be used in catalytic reduction is conventional one such as platinum catalyst (e.g., platinum plate, spongy platinum, platinum black, colloidal platinum, platinum oxide, platinum wire, etc.), palladium catalyst (e.g., spongy palladium, palladium black, palladium oxide, palladium on carbon, colloidal palladium, palladium on barium sulfate, palladium on barium carbonate, etc.), nickel catalyst (e.g., reduced nickel, nickel oxide, Raney nickel, etc.), cobalt catalyst (e.g., reduced cobalt, Raney cobalt, etc.), iron catalyst (e.g., reduced iron, Raney iron, Ullman iron, etc.), and the like.
The reduction is usually carried out in a conventional solvent such as water, alcohol (e.g., methanol, ethanol, isopropyl alcohol, etc.), tetrahydrofuran, dioxane, toluene, methylene chloride, ethylene dichloride, chloroform, N,N-dimethylformamide, N,N-dimethylacetamide and cyclohexane, a mixture thereof, or any other organic solvents which do not adversely affect the reaction.
When the above-mentioned acids to be used in chemical reduction are liquid, they can also be used as a solvent.
The reaction temperature of this reduction is not critical and the reaction is usually carried out under cooling to warming.
The compound (IV) or a salt thereof can be prepared by reacting the compound (VI) or its reactive derivative at the carboxy group, or a salt thereof, with the compound (VII) or its reactive derivative at the amino group, or a salt thereof.
Suitable salts of the compounds (VI) and (VII) may be the same as those exemplified for the compound (I).
The reaction is usually carried out in a conventional solvent such as water, acetone, dioxane, acetonitrile, chloroform, methylene chloride, ethylene chloride, tetrahydrofuran, ethyl acetate, N,N-dimethylformamide, pyridine and dichloromethane, a mixture thereof, or any other organic solvents which do not adversely affect the reaction.
This reaction can be carried out in the presence of an organic or inorganic base such as alkali metal (e.g., lithium, sodium, potassium, etc.), alkaline earth metal (e.g., calcium, etc.), alkali metal hydride (e.g., sodium hydride, etc.), alkaline earth metal hydride (e.g., calcium hydride, etc.), alkali metal hydroxide (e.g., sodium hydroxide, potassium hydroxide, etc.), Alkali metal carbonate (e.g., sodium carbonate, potassium carbonate, etc.), alkali metal bicarbonate (e.g., sodium bicarbonate, potassium bicarbonate, etc.), alkali metal alkoxide (e.g., sodium methoxide, sodium ethoxide, potassium tert-butoxide, etc.), alkali metal alkanoic acid (e.g., sodium acetate, etc.), trialkylamine (e.g., triethylamine, etc.), pyridine compound (e.g., pyridine, lutidine, picoline, 4-dimethylaminopyridine, etc.), quinoline, lithium diisopropylamide, and the like.
Suitable reactive derivative at the amino group of the compound (VII) may include Schiff""s base type imino or its tautomeric enamine type isomer formed by the reaction of the compound (VII) with a carbonyl compound such as aldehyde, ketone or the like; a silyl derivative formed by the reaction of the compound (VII) with a silyl compound such as bis(trimethylsilyl)acetamide, mono(trimethylsilyl)aetamide, bis(trimethylsilyl)urea or the like; a derivative formed by the reaction of the compound (VII) with phosphorus trichloride or phosgene, and the like.
Suitable reactive derivative at the carboxy group of the compound (VI) may include an acid halide, an acid anhydride, an activated amide, an activated ester, and the like. Suitable examples of the reactive derivative may be an acid chloride; an acid azide; a mixed acid anhydride with acid such as substituted phosphoric acid (e.g., dialkylphosphoric acid, phenylphosphoric acid, diphenylphosphoric acid, dibenzylphosphoric acid, halogenated phosphoric acid, etc.), dialkylphosphorous acid, sulfurous acid, thiosulfuric acid, sulfuric acid, sulfonic acid (e.g., methanesulfonic acid, etc.), aliphatic carboxylic acid (e.g., acetic acid, propionic acid, butyric acid, isobutyric acid, pivalic acid, pentanoic acid, isopentanoic acid, 2-ethylbutyric acid, trichloroacetic acid, etc.) or aromatic carboxylic acid (e.g., benzoic acid, etc.); a symmetrical acid anhydride; an activated amide with imidazole, 4-substituted imidazole, dimethylpyrazole, triazole or tetrazole; or an activated ester (e.g., cyanomethyl ester, methoxymethyl ester, dimethyliminomethyl [(CH3)2N+xe2x95x90CHxe2x80x94] ester, vinyl ester, propargyl ester, p-nitrophenyl ester, 2,4-dinitrophenyl ester, tri-chlorophenyl ester, pentachlorophenyl ester, mesylphenyl ester, phenyl azophenyl ester, phenyl thioester, p-nitrophenyl thioester, p-cresyl thioester, carboxymethyl thioester, pyranyl ester, pyridyl ester, piperidyl ester, 8-quinolyl thioester, etc.), or an ester with a N-hydroxy compound (e.g., N,N-dimethylhydroxylamine, 1-hydroxy-2-(1H)-pyridone, N-hydroxysuccinimide, N-hydroxyphthalimide, 1-hydroxy-1H-benzotriazole, etc.), and the like. These reactive derivative can be optionally be selected from them according to the kind of the compound (VI) to be used.
The reaction is preferably carried out in the presence of a conventional condensing agent such as N,Nxe2x80x2-dicyclohexylcarbodiimide; N-cyclohexyl-Nxe2x80x2morpholinoethylcarbodiimide; N-cyclohexyl-Nxe2x80x2-(4-di-ethylaminocyclohexyl)carbodiimide; N,Nxe2x80x2-diethylcarbodiimide; N,Nxe2x80x2-di-isopropylcarbodiimide; N-ethyl-Nxe2x80x2-(3-dimethylaminopropyl)carbodiimide; N,Nxe2x80x2carbonylbis-(2-methylimidazole); pentamethyleneketene-N-cyclo-hexylimine; diphenylketene-N-cyclohexylimine; ethoxyacetylene; 1-alkoxy-1-chloroethylene; trialkyl phosphite; ethyl polyphosphate; isopropyl polyphosphate; phosphorus oxychloride (phosphoryl chloride); phosphorus trichloride; diphenyl phosphorylazide; thionyl chloride; oxalyl chloride; lower alkyl haloformate (e.g., ethyl chloroformate, isopropyl chloroformate); triphenylphosphine; 2-ethyl-7-hydroxybenzisoxazolium salt; 2-ethyl-5-(m-sulfophenyl)isoxazolium hydroxide intramolecular salt; 1-(p-chlorobenzenesulfonyloxy)-6-chloro-1H-benzotriazole; 1-hydroxybenzotriazole; or so-called Vilsmeier reagent prepared by the reaction of N,N-dimethylformamide with thionyl chloride, phosgene, trichloromethyl chloroformate, phosphorus oxychloride or oxalyl chloride.
The reaction temperature is not critical, and the reaction is usually carried out under cooling.
The compound (X) or a salt thereof can be prepared by reacting the compound (VIII) or a salt thereof with the compound (IX) or a salt thereof.
Suitable salts of the compounds (VIII), (IX) and (X) may be the same as those exemplified for the compound (I).
The reaction is usually carried out in a conventional solvent such as water, acetone, dioxane, acetonitrile, chloroform, methylene chloride, ethylene chloride, tetrahydrofuran, ethyl acetate, N,N-dimethylformamide, pyridine and dichloromethane, a mixture thereof, or any other organic solvents which do not adversely affect the reaction.
This reaction can be carried out in the presence of an organic or inorganic base such as alkali metal (e.g., lithium, sodium, potassium, etc.), alkaline earth metal (e.g., calcium, etc.), alkali metal hydride (e.g., sodium hydride, etc.), alkaline earth metal hydride (e.g., calcium hydride, etc.), alkali metal hydroxide (e.g., sodium hydroxide, potassium hydroxide, etc.), alkali metal carbonate (e.g., sodium carbonate, potassium carbonate, etc.), alkali metal bicarbonate (e.g., sodium bicarbonate, potassium bicarbonate, etc.), alkali metal alkoxide (e.g., sodium methoxide, sodium ethoxide, potassium tert-butoxide, etc.), alkali metal alkanoic acid (e.g., sodium acetate, etc.), trialkylamine (e.g., triethylamine, etc.), pyridine compound (e.g., pyridine, lutidine, picoline, 4-dimethylaminopyridine, etc.), quinoline, lithium diisopropylamide, and the like.
The reaction is carried out in the presence of alkali metal halide (e.g., sodium iodide, potassium iodide, etc.), alkali metal thiocyanate (e.g., sodium thiocyanate, potassium thiocyanate, etc.), di(lower)alkyl azodicarboxylate (e.g., diethyl azodicarboxylate, diisopropyl azodicarboxylate, etc.), and the like.
The reaction is preferably carried out in the presence of a conventional condensing agent such as N,Nxe2x80x2-dicyclohexylcarbodiimide; N-cyclohexyl-Nxe2x80x2-morpholinoethylcarbodiimide; N-cyclohexyl-Nxe2x80x2-(4-di-ethylaminocyclohexyl)carbodiimide; N,Nxe2x80x2-diethylcarbodiimide; N,Nxe2x80x2-di-isopropylcarbodiimide; N-ethyl-Nxe2x80x2-(3-dimethylaminopropyl) carbodiimide; N,Nxe2x80x2-carbonylbis-(2-methylimidazole); pentamethyleneketene-N-cyclohexylimine; diphenylketene-N-cyclohexylimime; ethoxyacetylene; 1-alkoxy-1-chloroethylene; trialkyl phosphite; ethyl polyphosphate; isopropyl polyphosphate; phosphorus oxychloride (phosphoryl chloride); phosphorus trichloride; diphenyl phosphorylazide; thionyl chloride; oxalyl chloride; lower alkyl haloformate (e.g., ethyl chloroformate, isopropyl chloroformate); triphenylphosphine; 2-ethyl-7-hydroxybenzisoxazolium salt; 2-ethyl-5-(m-sulfophenyl)isoxazolium hydroxide intramolecular salt; 1-(p-chlorobenzenesulfonyloxy)-6-chloro-1H-benzotriazole; 1-hydroxybenzotriazole; or so-called Vilsmeier reagent prepared by the reaction of N,N-dimethylforamide with thionyl chloride, phosgene, trichloromethyl chloroformate, phosphorus oxychloride or oxalyl chloride.
The reaction temperature is not critical, and the reaction is usually carried out under cooling.
The compound (XII) or a salt thereof can be prepared by eliminating the hydroxy protective group of the compound (XI) or a salt thereof.
Suitable salts of the compounds (XI) and (XII) may be the same as those exemplified for the compound (I).
The reaction of this process can be carried out in a manner similar to that in Process 2.
The compound (XIII) or a salt thereof can be prepared by subjecting the compound (XII) or a salt thereof to amidation reaction.
Suitable salts of the compounds (XII) and (XIII) may be the same as those exemplified for the compound (I).
The reaction of this process can be carried out in a manner similar to that in Process 4.
The compound (IV) or a salt thereof can be prepared by reacting the compound (XIV) or a salt thereof with the compound (XV) or a salt thereof.
Suitable salts of the compounds (XIV) and (XV) may be the same as those exemplified for the compound (I).
The reaction of this process can be carried out in a manner similar to that in Process 1.
The compound (XVIII) or a salt thereof can be prepared by reacting the compound (XVI) or a salt thereof with the compound (XVII) or its reactive derivative at the carboxy group, or a salt thereof.
Suitable salts of the compounds (XVI), (XVII) and (XVIII) may be the same as those exemplified for the compound (I).
Suitable reactive derivative at the amino group of the compound (XVII) may include Schiff""s base type imino or its tautomeric enamine type isomer formed by the reaction of the compound (XVII) with a carbonyl compound such as aldehyde, ketone or the like; a silyl derivative formed by the reaction of the compound (XVII) with a silyl compound such as bis(trimethylsilyl)acetamide, mono(trimethylsilyl)acetamide, bis(trimethylsilyl)urea or the like; a derivative formed by the reaction of the compound (XVII) with phosphorus trichloride or phosgene, and the like.
The reaction is usually carried out in a conventional solvent such as water, acetone, dioxane, acetonitrile, chloroform, methylene chloride, ethylene chloride, tetrahydrofuran, ethyl acetate, N,N-dimethylformamide, pyridine and dichloromethane, a mixture thereof, or any other organic solvents which do not adversely affect the reaction.
This reaction can be carried out in the presence of an organic or inorganic base such as alkali metal (e.g., lithium, sodium, potassium, etc.), alkaline earth metal (e.g., calcium, etc.), alkali metal hydride (e.g., sodium hydride, etc.), alkaline earth metal hydride (e.g., calcium hydride, etc.), alkali metal hydroxide (e.g., sodium hydroxide, potassium hydroxide, etc.), alkali metal carbonate (e.g., sodium carbonate, potassium carbonate, etc.), alkali metal bicarbonate (e.g., sodium bicarbonate, potassium bicarbonate, etc.), alkali metal alkoxide (e.g., sodium methoxide, sodium ethoxide, potassium tert-butoxide, etc.), alkali metal alkanoic acid (e.g., sodium acetate, etc.), trialkylamine (e.g., triethylamine, etc.), pyridine compound (e.g., pyridine, lutidine, picoline, 4-dimethylaminopyridine, etc.), quinoline, lithium diisopropylamide, and the like.
The reaction is carried out in the presence of alkali metal halide (e.g., sodium iodide, potassium iodide, etc.), alkali metal thiocyanate (e.g., sodium thiocyanate, potassium thiocyanate, etc.), di(lower)alkyl azodicarboxylate (e.g., diethyl azodicarboxylate, diisopropyl azodicarboxylate, etc.), and the like.
The reaction is preferably carried out in the presence of a conventional condensing agent such as N,Nxe2x80x2-dicyclohexylcarbodiimide; N-cyclohexyl-Nxe2x80x2-morpholinoethylcarbodiimide; N-cyclohexyl-Nxe2x80x2-(4-di-ethylaminocyclohexyl)carbodiimide; N,Nxe2x80x2-diethylcarbodiimide; N,Nxe2x80x2-di-isopropylcarbodiimide; N-ethyl-Nxe2x80x2-(3-dimethylaminopropyl)carbodiimide; N,Nxe2x80x2carbonylbis-(2-methylimidazole); pentamethyleneketene-N-cyclohexylimine; diphenylketene-N-cyclohexylimine; ethoxyacetylene; 1-alkoxy-1-chloroethylene; trialkyl phosphite; ethyl polyphosphate; isopropyl polyphosphate; phosphorus oxychloride (phosphoryl chloride); phosphorus trichloride; diphenyl phosphorylazide; thionyl chloride; oxalyl chloride; lower alkyl haloformate (e.g., ethyl chloroformate, isopropyl chloroformate); triphenylphosphine; 2-ethyl-7-hydroxybenzisoxazolium salt; 2-ethyl-5-(m-sulfophenyl) isoxazolium hydroxide intramolecular salt; 1-(p-chlorobenzenesulfonyloxy)-6-chloro-1H-benzotriazole; 1-hydroxybenzotriazole; or so-called Vilsmeier reagent prepared by the reaction of N,N-dimethylforamide with thionyl chloride, phosgene, trichloromethyl chloroformate, phosphorus oxychloride or oxalyl chloride.
The reaction temperature is not critical, and the reaction is usually carried out under cooling.
The compound (XX) or a salt thereof can be prepared by eliminating the hydroxy protective group of the compound (XIX) or a salt thereof.
Suitable salts of the compounds (XIX) and (XX) may be the same as those exemplified for the compound (I).
The reaction of this process can be carried out in a manner similar to that in Process 2.
The compound (XXII) or a salt thereof can be prepared by subjecting the compound (XXI) or a salt thereof to solvolysis.
Suitable salts of the compounds (XXII) and (XXI) may be the same as those exemplified for the compound (I).
The solvolysis is carried out in a conventional solvent such as water, alcohol (e.g., methanol, ethanol, etc.), a mixture thereof, or any other organic solvents which do not adversely affect the reaction.
The reaction temperature is not critical, and the reaction is usually carried out under cooling to heating.
The compounds obtained can be isolated and purified by a conventional method such as pulverization, recrystallization, column chromatography, reprecipitation and the like.
The object compounds can be transformed into their salts in a conventional manner.
It is to be noted that the object compounds may include one or more stereoisomers due to asymmetric carbon atoms, and all of such isomers and mixtures thereof are included within the scope of this invention.
Collagenases initiate the degradation of collagen in vertebrates and, in addition to their normal function in the metabolism of connective tissue and wound healing, they have been implicated to be involved in a number of pathological conditions such as joint destruction in rheumatoid arthritis, periodontal disease, corneal ulceration, tumor metastasis, osteoarthritis, decubitus restenosis after percutaneous transluminal coronary angiopsty, osteoporosis, proriasis, chronic active heatitis, autoimmune keratitis, and the like, and therefore the compounds of the present invention are useful for treating and/or preventing such pathological conditions.
For therapeutic purposes, the compounds and pharmaceutically acceptable salts thereof of the present invention can be used in the form of a pharmaceutical preparation containing, as an active ingredient, one of said compounds in admixture with a pharmaceutically acceptable carrier such as an organic or inorganic solid or liquid excipient suitable for oral, parenteral or external administration. The pharmaceutical preparations may be capsules, tablets, dragees, granules, solutions, suspensions, emulsions, sublingual tablets, suppositories, ointments, and the like. If desired, there may be included, in these preparations, auxiliary substances, stabilizing agents, wetting agents, emulsifying agents, buffers and other commonly used additives.
While the dose of the compound will vary depending upon the age and condition of patient and the like, in the case of intravenous administration, a daily dose of 0.01-100 mg of the active ingredient per kg weight of a human being, and in the case of intramuscular administration, a daily dose of 0.05-100 mg of the same per kg weight of a human being, or in the case of oral administration, a daily dose of 0.1-100 mg of the same per kg weight of a human being, is generally given for the treatment of MMP or TNFxcex1 mediated diseases.
In order to illustrate the usefulness of the object compound, the pharmacological test data of a representative compound of the compound are shown in the following.
1. Test Method
Human collagenase was prepared from the culture medium of human skin fibroblast stimulated with interleukin-1xcex2 (1 ng/ml). Latent collagenase was activated by incubation with trypsin (200 xcexcg/ml) at 37xc2x0 C. for 60 minutes and the reaction was stopped by adding soybean trypsin inhibitor (800 xcexcg/ml). Collagenase activity was determined using FTTC-labeled calf skin type I collagen. FTTC-collagen (2.5 mg/ml) was incubated at 37xc2x0 C. for 120 minutes with the activated collagenase and test compound in 50 mM Tris buffer (containing 5 mM CaCl2, 200 mM NaCl and 0.02% NaN3, pH 7.5). After stopping the enzyme reaction by adding the equal volume of 70% ethanol-200 mM Tris buffer (pH 9.5), the reaction mixture was centrifuged, and collagenase activity was estimated by measuring the fluorescence intensity of supernatant at 495 nm (excitation) and 520 nm (emission).
2. Test Compound
Compound of Example 5
3. Test Result